Regulation of Cortical Neurogenesis by MED13L via Transcriptional Priming and its Implications for MED13L Syndrome

MED13L is highly susceptible to neurodevelopmental disorders, yet the underlying developmental mechanisms remain poorly understood. We developed a gene knockout mouse model of MED13L syndrome to elucidate these mechanisms. Homozygous Med13l-null mice exhibit neonatal lethality and severe cortical neurogenesis deficits due to impaired differentiation of neural progenitors. In contrast, heterozygous Med13l-null mice are viable but display characteristic behavioral deficits of MED13L syndrome, including impaired learning and memory, reduced motor coordination, and heightened anxiety. Heterozygous mice also present with microcephaly and simplified neuronal morphology in the motor cortex. Conditional knockout of Med13l in the forebrain pyramidal lineage corroborated the motor and histological deficits observed. Proteomic, transcriptomic, and single-cell RNA sequencing analyses suggest that MED13L regulates cortical neurogenesis by priming developmental genes for transcriptional activation as a component of the mediator complex. These findings provide insights into the molecular and neurodevelopmental underpinnings of MED13L syndrome, paving the way for potential therapeutic strategies.